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After a fight with classic Spider-Man, the Gold Goblin starts bringing alternate versions of the Sinister Six and alternate versions of himself via a blue portal in the sky to bring an end to all Spider-Men around the multiverse with the help of ISO-8.

Spider-Man is contacted by Nick Fury Jr. and tells him of the Goblin's plan and S.H.I.E.L.D's countermeasure to combat the alternate Sinister Six by opening their own portal and bringing alternate Spider-Men to stop every version of the Sinister Six from destorying New York and stealing ISO-8. They do this first by bringing the Mangaverse Spider-Man, and it is then up to the player to bring other Spider-Men through and save New York and all other Spider-Men from falling to the hands of the mutiverse Sinister Six.